Professor Li Jianming/Gao Tianming reveals that the intestinal flora regulates vitamin B6 metabolism and mediates autistic behaviors

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In most patients with autism, there are changes in intestinal microbes and severe gastrointestinal symptoms
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Intestinal flora transplantation can significantly improve the gastrointestinal symptoms and autism symptoms of 7 to 16-year-old patients with autism.
What is more surprising is that this treatment effect can be maintained for 2 years
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EPHB6, a member of the Eph receptor tyrosine kinase family, has mutations in this gene in patients with autism
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Eph/ephrin signals regulate intestinal epithelial development and homeostasis
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In August 2020, the team of Professor Li Jianming from Sun Yat-sen Memorial Hospital of Sun Yat-sen University and Professor Gao Tianming from Southern Medical University published an article in Microbiome, revealing that the gut microbiota mediates autistic behaviors by regulating the metabolism of vitamin B6
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EPHB6 knockout mice exhibit autism-like behaviors.
EPHB6 knockout mice exhibit autism-like behavior disorders such as social disorders and repetitive stereotypes, as well as anxiety-like behaviors
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In addition, the expression of pro-inflammatory factors in the colon of the knockout mice is increased, the expression of anti-inflammatory factors is decreased, the permeability of the intestine is increased, and the expression of tight junction molecule proteins is also decreased
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This indicates that knocking out EPHB6 causes autism-like behavior while causing intestinal disorders in mice
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Microbial sequencing technology found that the fecal microbiota of EPHB6 knockout mice was significantly different from that of normal mice, which was mainly manifested in the significant decrease in the number of deferrobacteria and mucispirillum in the feces of knockout mice
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Interestingly, the difference in intestinal microbes of EPHB6 knockout mice and autism-like behavior disorder are greatly correlated in time: at the level of intestinal flora, EPHB6 knockout mice at the age of 4 months show the same The flora of normal mice is different; EPHB6 knockout mice at the age of 4 months only show social behavior disorder, and knockout mice at 3 months old do not show this behavior disorder
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This temporal relationship suggests that there may be a relationship between abnormal behaviors in EphB6-deficient mice and intestinal microbial disturbances
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The researchers transplanted the intestinal flora of 8-week-old EPHB6 knockout mice into 3-week-old sterile mice (EPHB6 is normally expressed), and these sterile mice exhibited autistic behavior disorder 3 weeks after transplantation
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What's more interesting is that the intestinal flora of knockout mice can still show the above behavioral disorders after adult sterile mice (6 weeks of age)
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After antimicrobial treatment, these sterile mice will not show autistic behavior disorder
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These results indicate that the intestinal flora plays a key role in the pathogenesis of autism
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Vitamin B6 in the body is mainly derived from diet and intestinal bacterial synthesis, and then is absorbed in the intestinal tract
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Researchers found that the vitamin B6 metabolic pathway in the prefrontal cortex of EPHB6 knockout mice was disturbed, and the levels of pyridoxamine (PM) and pyridoxal 5'-phosphate (PLP, the main metabolically active form of vitamin B6) decreased
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As a cofactor, vitamin B6 participates in more than 140 biochemical reactions in cells, including the biosynthesis and catabolism of amino acids and neurotransmitters
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Researchers injected pyridoxal 5'-phosphate into the intraperitoneal cavity of EPHB6 knockout mice, which can significantly improve social disorders, but it is not effective for repetitive stereotyped behaviors
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High performance liquid chromatography experiments found that the level of dopamine in the prefrontal cortex of EPHB6 knockout mice was decreased and the level of serotonin (5-HT) was increased
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The dopamine levels in the prefrontal cortex of sterile mice were also reduced after transplantation of the intestinal flora of the knockout mice.
Intraperitoneal injection of pyridoxal 5'-phosphate can increase the level of dopamine in the prefrontal cortex of EPHB6 knockout mice
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In addition, injection of dopamine type 1 receptor agonists into the prefrontal cortex of EPHB6 knockout mice can improve social disorders, but dopamine type 2 receptor agonists do not show this therapeutic effect
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After sterile mice received a diet deficient in vitamin B6, the concentration of dopamine in the prefrontal cortex decreased
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Studies have shown that dopamine type 1 receptors can regulate the inhibitory effect of inhibitory neurons in the prefrontal cortex
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The spontaneous inhibitory postsynaptic current in the prefrontal cortex of EPHB6 knockout mice is reduced, and normal mice also show this disorder after receiving the gut flora of knockout mice
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Dopamine type 1 receptor agonists can effectively reverse this inhibitory synaptic transmission disorder, indicating that the intestinal flora can be controlled by dopamine to knock out the synaptic transmission dysfunction caused by EPHB6
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In summary, this article reveals that the intestinal microbiota-mediated vitamin B6 metabolism disorder causes autism-like behavioral disorders by reducing dopamine levels and excitatory/inhibitory imbalances in the prefrontal cortex
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[References] 1.
https://doi.
org/10.
1186/s40168-020-00884-z, the pictures in the text are all from the references